Asian Case Reports in Veterinary Medicine
Vol. 08  No. 04 ( 2019 ), Article ID: 32227 , 8 pages
10.12677/ACRPVM.2019.84007

Antimicrobial Peptides and the Gastrointestinal Health of Weaned Piglets

Yantao Chen, Yanhong Zhang, Changzhong Liu, Gangcai Wei, Yanzhao Xu, Feng Guo*, Kun Zhao*

College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang Henan

Received: Sep. 1st, 2019; accepted: Sep. 12th, 2019; published: Sep. 19th, 2019

ABSTRACT

In the modern pig industry, the immune function of piglets has not yet been mature when they are weaned at 3 to 4 weeks of age, and piglets are always challenged by postweaning stress. Therefore, in-feed antibiotic use is a common practice for improving growth performance and preventing disease of weaned piglets. However, the problem of drug residues and drug resistance caused by antibiotic abuse has seriously threatened livestock production and human health, forcing people to find alternatives to antibiotics. Antibacterial peptides have become a promising alternative for antibiotics because they have many advantages, such as broad antimicrobial spectrum, not easy to produce drug resistance, and almost non-toxic effects. Recent progresses on antimicrobial peptide in weaned piglets production will be discussed in this review including the reducing susceptibility to disease, growth promoting, ameliorating intestinal microecology, improvement of the intestinal mucosa, improving the immune function of piglets and prospects.

Keywords:Antimicrobial Peptide, Weaned Piglets, Intestinal Tract, Growth, Health

抗菌肽与断奶仔猪的肠道健康

陈燕涛,张艳红,刘长忠,魏刚才,徐彦召,郭锋*,赵坤*

河南科技学院 动物科技学院,河南 新乡

收稿日期:2019年9月1日;录用日期:2019年9月12日;发布日期:2019年9月19日

摘 要

现代养殖模式下,断奶仔猪的免疫功能尚未发育成熟,加之断奶应激的负面影响较大,因此,为了促进断奶仔猪的生长、防治疾病,生产中通常会使用抗生素。但抗生素滥用造成的药物残留、病原微生物的耐药性等问题,严重威胁畜牧生产和人类健康,迫使人类寻找抗生素的替代物。由于抗菌肽具有抗菌谱广、不易产生耐药性、几乎无毒副作用等优点,使其成为了极有希望替代抗生素的物质。本文从抗菌肽抗病、促生长、改善肠道微生态、改善肠道粘膜,以及提高机体免疫功能等方面综述其在断奶仔猪中的研究进展。

关键词 :抗菌肽,断奶仔猪,肠道,生长,健康

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

现代养猪产业模式下,仔猪通常在3~4 w即已断奶,而其免疫功能大约到7 w后才能发育成熟 [1]。因此,断奶仔猪极易受到病原微生物的感染 [2] [3] [4] ,加之断奶应激会降低仔猪的免疫力、影响肠道的消化吸收功能,从而造成腹泻、生长缓慢、多种疾病,甚至死亡 [5] [6] ,造成巨大的经济损失。

为了应对断奶对仔猪造成的不良影响,生产中广泛使用抗生素,以增加饲养效率、促进动物生长和预防疾病 [7] [8]。不可否认,抗生素对畜牧业的发展起了非常重要的作用,特别是在饲养条件落后的年代和国家地区。但是,由于抗生素的滥用导致畜产品抗生素残留的问题日益突出,同时也产生了大量的耐药菌,甚至超级细菌 [9] [10]。更为严峻的是,畜产品中残留的抗生素可以通过食物链传递给人类,威胁人类的健康 [11] [12] [13] [14]。因此,开发一些新型、安全、高效的抗菌素替代品显得非常迫切。抗菌肽具有抗菌谱广、无污染、几乎无毒副作用、不易产生耐药性等优点,其俨然已成为抗生素的极佳替代品 [15] [16]。

抗菌肽(antimicrobial peptides, AMPs)是一类由几十个氨基酸组成的短链多肽,可从植物、动物和人的组织细胞中提取、分离、纯化得到 [17] [18] [19] [20]。抗菌肽具有广泛的抗细菌、抗病毒、抗真菌、抗寄生虫、抗肿瘤以及提高机体免疫力等功能 [21] - [28] ,在人和动物的先天免疫以及非特异性免疫过程中发挥重要的作用 [18]。本文从抗菌肽抗病、促生长、改善肠道微生态、改善肠道粘膜、提高机体免疫功能、抗菌肽与益生菌等方面做一综述。

2. 抗病、促生长

很多研究表明仔猪断奶前后饲料中添加抗菌肽,能够促进其生长发育、增强抗病能力、降低患病率,提高经济效益。Yoon等在饲料中添加60 mg∙kg−1人工合成的抗菌肽A3或P5,断奶仔猪的平均日增重和饲料转换率均显著高于对照组的(p < 0.05) [29] ;Yu等给断奶仔猪饲料中添加0.5、1.0、2.0 mg∙kg−1的抗菌肽小菌素J25,同样发现试验组仔猪的平均日增重、平均日采食量和饲料转换率显著提高(p < 0.05) [30]。Xiong等给5个猪场的饲料中添加乳铁蛋白、天蚕抗菌肽、防御肽和菌丝霉素组成的复合抗菌肽,与对照组相比,饲料中添加2 g∙kg−1抗菌肽也可以显著提高断奶仔猪的平均日增重、平均日采食量以及饲料转换率(p < 0.05) [31]。断奶期间因仔猪肠道发育的不完善,有害菌增多引起的仔猪腹泻是造成经济损失的重要方面。很多研究发现,饲料中添加抗菌肽在提高断奶仔猪生长性能的同时,还能有效地降低仔猪的腹泻率(p < 0.05) [30] [31] [32]。Zhang等以断奶仔猪为研究对象,发现爬行动物源的抗菌肽Cathelicidin-衍生肽对LPS引起的肠炎具有保护作用 [33]。复合抗菌肽亦能有效地缓解因口服脱氧雪腐镰刀菌烯醇导致的肠道损伤(p < 0.05),降低肠道炎症反应 [34]。

3. 改善肠道微生态

肠道微生态系统是动物最主要、最复杂的微生态系统,稳定的肠道微生态系统对动物正常生理功能的维持和机体抵抗病原微生物的感染极为重要 [35]。研究表明,断奶应激会使仔猪肠道中大肠杆菌数量增加,有益菌数量下降,且越早断奶有益菌下降的幅度越大,这严重破坏了仔猪肠道微生态系统的平衡 [36] [37]。更为严峻的是,大幅增加的大肠杆菌等有害菌会产生大量毒素,最终损害肠道健康 [38]。而抗菌肽可以抑制或杀死有害菌,并增加益生菌的数量。

早期在小鼠上的研究发现,给小鼠饲喂含2 mg∙mL−1牛乳铁蛋白的配方奶,可以显著增加其肠道中双歧杆菌的数量(p < 0.05) [39]。之后,研究人员给仔猪饲喂含20 mg∙g−1人乳铁蛋白和2 mg∙g−1牛乳铁蛋白的配方奶,发现同样可以增加仔猪肠道中双歧杆菌的数量(p < 0.05) [40] ;Yoon等在饲料中添加人工合成的抗菌肽A3或P5,发现断奶仔猪回肠、盲肠以及粪便中的大肠杆菌和梭状芽孢杆菌的数量显著低于对照组的(p < 0.05) [29] ;汪以真(博士论文)研究发现,饲料中添加表达重组乳铁蛋白基因的蚕蛹,可以显著增加仔猪肠道中乳酸杆菌和双歧杆菌的数量(p < 0.05),同时抑制仔猪肠道中大肠杆菌和沙门氏菌的生长(p < 0.05) [41] ;Wu等给仔猪饲喂添加有天蚕菌素的饲料,其回肠中的好氧菌的数量明显降低,同时厌氧菌的数量增加(p < 0.05) [32]。

4. 改善肠道粘膜

断奶仔猪的肠道粘膜尚未发育完全,断奶应激会引起仔猪肠道黏膜形态结构改变、肠上皮屏障通透性增加、消化吸收功能降低、黏液层厚度下降、免疫功能紊乱等 [42] [43] ,而研究发现抗菌肽可以在这些方面对肠道粘膜具有很好的改善作用。易宏波(博士论文)以腹泻的断奶仔猪为研究对象,发现腹腔注射0.6 mg∙kg−1抗菌肽CWA可以显著改善断奶仔猪的小肠绒毛形态,缓解结肠水肿现象,并显著增加仔猪空肠和回肠的绒毛高度/隐窝深度比(p < 0.05) [44]。其他学者在饲料中分别添加抗菌肽天蚕素、A3、P5,发现均可以改善断奶仔猪的小肠绒毛长度以及其与隐窝深度的比值 [29] [32]。另外,给予断奶仔猪大肠杆菌攻毒后,灌服0.25 mg抗菌肽buforin II,每日两次并持续3 w,仔猪小肠的紧密连接蛋白和肠道保护因子表达显著增加(p < 0.05),表明了防御素对断奶仔猪肠道黏膜完整性的保护作用 [45]。饲粮中添加60 mg∙kg−1抗菌肽P5或A3能够显著提高断奶仔猪的全肠道表面消化率和氨基酸回肠末端表面消化率(p < 0.05) [29] [46]。断奶仔猪腹腔注射LPS后再给予腹腔注射抗菌肽C-BF,仔猪肠道损伤明显减轻,空肠的炎症细胞浸润显著降低(p < 0.05) [33]。断奶仔猪食用含有脱氧雪腐镰刀菌烯醇(呕吐毒素)的饲料会导致其小肠通透性增大、绒毛损伤、上皮细胞凋亡、以及细胞内蛋白合成的抑制,而饲料中添加复合抗菌肽能够有效地缓解这些影响(p < 0.05) [34]。

5. 提高机体免疫功能

抗菌肽除了可以抑制并杀死病原微生物,还具有重要的免疫调节功能。在不同物种上的研究证实了抗菌肽具有调节趋化因子表达并招募免疫细胞、调节炎症反应、激活免疫细胞等免疫调节功能 [47]。抗菌肽在断奶仔猪上的应用也显示出对其体液免疫、细胞免疫以及细胞因子表达的调节作用。Ren等在日粮中添加抗菌肽(猪的防御肽和苍蝇抗菌肽按1:1混合),发现试验组仔猪脾脏中G0/G1期细胞显著减少(p < 0.05),S期和G2+M期细胞显著增加,细胞增殖指数明显增大(p < 0.05),凋亡细胞比例明显降低。另外,外周血CD3+、CD3+CD4+、以及CD4+CD8+ T细胞比例均显著增加(p < 0.05),说明抗菌肽能够显著提高断奶仔猪脾脏细胞以及T细胞的增殖能力,有效改善其细胞免疫功能 [48]。Shan等在饲料中添加1000 mg∙kg−1乳铁蛋白也能显著提高断奶仔猪脾脏淋巴细胞的增殖能力,同时发现血清中IgG、IgA、IgM的水平显著升高了(p < 0.05) [49]。Wu等给断奶仔猪饲喂添加了天蚕菌素的饲料,发现仔猪的空肠中分泌的IgA水平以及血清中IgA、IgG水平较对照组显著升高(p < 0.05) [32]。这些结果表明,抗菌肽对断奶仔猪细胞及体液免疫具有积极的调节作用。细胞因子是动物机体在发生炎症和免疫应答过程中由免疫细胞产生,通过与受体作用参与机体免疫调节作用的小分子蛋白质 [50] [51]。很多研究表明,断奶仔猪饲喂含有抗菌肽的日粮能够提高其血清中细胞因子的水平。例如,在Shan的研究中即发现乳铁蛋白能够提高仔猪血清中IL-2的含量(p < 0.05) [49] ,而在Wu的研究中证实天蚕菌素能够提高断奶仔猪血清中IL-1β和Il-6的水平(p < 0.05) [32]。袁威等(2015)给予断奶仔猪饲喂添加了复合抗菌肽(猪防御素和苍蝇抗菌肽按1:1混合)的日粮28 d,也发现仔猪血清中IL-2、IL-4、IL-6、IFNγ以及TNFα的水平显著增加(p < 0.05) [52]。

6. 抗菌肽与益生菌

在改善人和动物肠道健康方面,益生菌可谓是功不可没。益生菌能调节肠道菌群平衡,防治腹泻,且价格低廉,目前已被广泛应用于医疗保健和畜牧业 [53] [54]。另外,益生菌本身就是人和动物胃肠道微生态系统的重要成员,有的益生菌可以分泌乳酸、乙酸、丙酸和丁酸等,从而保持了胃肠道的低pH值,进而抑制有害菌的粘附、生长、繁殖,同时还促进其他益生菌的增殖,大部分益生菌还能产生消化酶以促进动物胃肠道的消化吸收。例如,Hou等将9窝仔猪标准化至8头哺乳仔猪进行试验,随机分为3组,分别进行短期添加(1~5 d,持续5 d)、早期间歇性添加(从1日龄到17日龄,每隔4 d添加一次) 1.7 × 1010 CFU罗伊氏乳杆,对照组饲喂4 ml 0.1%的蛋白胨水。结果显示,在14日龄时,处理组仔猪回肠中的双歧杆菌的数目显著高于对照组(p < 0.05),短期处理组的仔猪在7日龄时以及早期间歇性处理组的仔猪在14日龄时,肠道中的乳酸浓度增加、pH降低(p < 0.05) [55]。另有研究报道,饲料中添加瑞特乳酸菌15007,可促进IPEC-J2细胞中以及仔猪肠道中beta-defensin-2、pBD3、pBD114和pBD129等抗菌肽的表达(p < 0.05),并且可以通过增加丁酸浓度进而改善仔猪肠道的健康状况 [56]。基于抗菌肽和益生菌各自的优势以及相互的促进作用,Xu等在仔猪饲料中添加表达融合抗菌肽(猪的beta-defensin-2和天蚕素P1融合肽)的枯草芽孢杆菌,结果发现其可显著促进仔猪的生长(p < 0.05),并降低仔猪的腹泻(p < 0.05) [57]。虽然试验并不能确定到底是枯草芽孢杆菌,还是猪的beta-defensin-2和天蚕素P1融合肽,亦或是两者的协同作用,最终取得如此好的效果,但作者的研究为我们提供了一个新颖的研究思路。

7. 展望

当下,全面禁抗已进入倒计时。作为抗生素的替代物或新型的饲料添加剂,抗菌肽有诸多优势,但同时也有一些问题值得深入思考和研究。比如,抗菌肽的生产问题,从动植物中提取得率太低,而人工合成的成本又过于昂贵 [58] ,因此生物工程生产方式将是满足未来需求的最佳途径;再如,抗菌肽的使用问题,如前文所述,不同抗菌肽的使用剂量不同,但投放手段多采取最易操作的饲料添加,然而如何有效避开胃肠道中各种消化酶对抗菌肽的酶解作用以保持其活性仍需大量的研究;人医上有些肠道药物采取肠溶性包衣的形式,比如美沙拉嗪,可保证药物顺利通过胃中的酸性环境,进入肠道,在碱性的肠液中崩解包衣、暴露药物,但此类工艺无疑会加大抗菌肽的生产成本;另外,目前的研究,除了如前所述,抗菌肽可以抑制动物腹泻或炎症外,也有一些报道的结果与之相反。Severino等在用盲肠结扎和穿刺诱导的败血症小鼠上发现,敲除抗菌肽cathelicidin基因的小鼠比野生型小鼠的存活率高(p < 0.05) [59]。Hashimoto等研究发现,给DSS诱导的小鼠腹腔注射抗菌肽HNP-1,会加重小鼠的结肠炎(p < 0.05) [60] ,提示在结肠炎中HNP-1可能发挥了促炎作用。另有研究者检测到,溃疡性结肠炎患者的肠道上皮细胞中抗菌肽hBD-2和hBD-3的表达量分别较正常人的提高了1000倍和300倍 [61] [62] ,但不幸的是,如此高水平表达的抗菌肽却无法有效遏制细菌对肠道粘膜的持续入侵 [63]。因此,不同种类的抗菌肽与人和动物肠道炎症之间的关系仍需进行广泛而深入的研究。

此外,抗菌肽与益生菌的联合使用也应该得到重视。益生菌有诸多优势,如无致病性、无毒性、无残留、不产生LPS、价格低廉,因此,将益生菌改造成工程菌用以表达抗菌肽,可谓一举两得。既能体现出前文所述益生菌的优良功效,又可使成功定植在肠道中的益生菌持续表达抗菌肽。目前,类似的研究还很少,但可以预见,将益生菌作为工程菌来表达抗菌肽并添加至饲料或饮水中应该是非常经济高效的生产和投放抗菌肽的方法,其成熟的研究成果势必会更好地为畜牧业以及人类的健康服务。

致谢

本论文从撰写提纲到最终成稿,得到了胡建和教授的“抗菌肽与新兽药”团队的大力支持,在此表示由衷的感谢!也感谢研究生胡斌在文字校对上做出的贡献!最后,感谢下列基金项目的大力支持!

基金项目

本论文得到了国家自然科学基金(31672559)、河南省高校科技创新团队支持计划(15IRTSTHN)和河南省高等学校重点科研项目计划(17B230002)的支持。

文章引用

陈燕涛,张艳红,刘长忠,魏刚才,徐彦召,郭 锋,赵 坤. 抗菌肽与断奶仔猪的肠道健康
Antimicrobial Peptides and the Gastrointestinal Health of Weaned Piglets[J]. 亚洲兽医病例研究, 2019, 08(04): 47-54. https://doi.org/10.12677/ACRPVM.2019.84007

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  64. NOTES

    *通讯作者。

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